Project Summary This proposal supports the bioinformatics needs of two NCI funded Outstanding Investigators at the Northwestern University Department of Biochemistry and Molecular Genetics. One project, with Dr. Ali Shilatifard, examines the role of mutations in histone modifiers such as MLL in the progression of cancer. A recent discovery on the stabilization of mutant proteins relative to wildtype gives insight into one cause of disease and a new target for cancer therapy. Another project examines the role of transcription elongation factors in cancer development. These proteins are often fused to MLL in leukemia, but it is not clear why general transcriptional regulators lead to specific types of cancer. A third project examines another chromatin protein, histone H3, and how mutation of H3K27 to methionine can lead to specific types of pediatric brain cancer. Here too, new understanding of the molecular mechanism of the disease has led to a new line of therapy for this currently incurable and devastating childhood cancer. A fourth project, in collaboration with Dr. Marcus Peter, examines another fundamental cellular process, DISE, and how it might be exploited to trigger cell death specifically in cancer cells. The common thread in all of these projects is the need for careful, biologically motivated computational analysis to make sense of next generation sequencing data that is essential in examining the function of cancer cells, both before and after perturbation. Dr. Bartom will provide this analysis, and her expertise in both biology and computation will allow cancer biologists to extract more insight from their data, and to maintain a high standard of scientific rigor and reproducibility.